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  • CLASSES

    MS Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Anti-inflammatory agent and inducer of the nuclear 1 factor (erythroid- derived 2)–like 2 (Nrf2) antioxidant response pathway
    Used for the treatment of adults with relapsing forms of multiple sclerosis
    Oral agent with unique neuroprotective properties

    COMMON BRAND NAMES

    Tecfidera

    HOW SUPPLIED

    Dimethyl fumarate/Tecfidera Oral Cap: 120mg, 240mg, 120-240mg

    DOSAGE & INDICATIONS

    For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
    Oral dosage
    Adults

    120 mg PO twice daily for 7 days, then 240 mg PO twice daily. Consider a temporary dose reduction to 120 mg PO twice daily for individuals who do not tolerate the maintenance dose. Resume the recommended dose of 240 mg PO twice daily within 4 weeks. Consider discontinuation of therapy in patients unable to tolerate return to the maintenance dose.

    MAXIMUM DOSAGE

    Adults

    480 mg/day PO.

    Geriatric

    480 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Administer the capsules intact. Do not crush or sprinkle the capsule contents on food. Also, instruct the patient to not chew the capsule.
    The capsules may be taken with or without food, but administration with food may reduce the incidence of flushing.

    STORAGE

    Tecfidera:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Dimethyl fumarate is contraindicated in patients who have demonstrated hypersensitivity to dimethyl fumarate or any of its excipients. There have been reports of anaphylaxis and angioedema associated with dimethyl fumarate therapy which may occur after the first dose or any time during treatment.

    Immunosuppression

    Dimethyl fumarate use in patients with immunosuppression may be inadvisable, as the drug may decrease lymphocyte counts and has not been studied in patients with pre-existing low lymphocyte counts. Obtain a complete blood count (CBC) including lymphocyte count before dimethyl fumarate initiation. A CBC including lymphocyte count should also be obtained 6 months after treatment initiation, every 6 to 12 months thereafter, and as clinically indicated.

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) has occurred with dimethyl fumarate. As PML can be fatal, instruct patients to notify their healthcare provider immediately if they notice new or worsening neurological signs or symptoms such as ataxia, visual changes, or confusion. Similarly, suspect PML in any patient presenting with neurological symptoms; discontinue dimethyl fumarate at the first sign or symptom of PML and perform a diagnostic evaluation. As PML has occurred in the presence of prolonged lymphopenia, obtain a complete blood count (CBC) including lymphocyte count before dimethyl fumarate initiation. A CBC including lymphocyte count should also be obtained 6 months after treatment initiation, every 6 to 12 months thereafter, and as clinically indicated. Consider MRI monitoring for signs that may be consistent with PML. MRI findings suggestive of PML and detection of JC virus (JCV) DNA in the CSF in the absence of clinical signs and symptoms of PML have been reported in patients treated with other multiple sclerosis medications; many cases progressed to symptomatic PML. Promptly investigate any suspicious findings to allow for early diagnosis.

    Hepatic disease, hepatotoxicity

    Use dimethyl fumarate with caution in patients with hepatic disease. Postmarketing cases of clinically significant liver injury have been reported with dimethyl fumarate. The onset of hepatotoxicity has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal (ULN) and elevation of total bilirubin to greater than 2-fold the ULN have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients. Obtain liver function tests (LFTs) such as serum aminotransferase, alkaline phosphatase, and total bilirubin concentrations prior to and during treatment, as clinically indicated. Discontinue treatment if clinically significant liver injury induced by dimethyl fumarate is suspected.

    Pregnancy

    No adequate and well-controlled studies of the use of dimethyl fumarate in pregnant women exist, but animal studies showed adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function when dimethyl fumarate was administered during pregnancy at clinically relevant doses. Animal reproductive studies are not always predictive of human response. Only use dimethyl fumarate during pregnancy if the potential benefit justifies the potential risk to the fetus. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to dimethyl fumarate; information about the registry can be obtained at www.tecfiderapregnancyregistry.com or by calling 1-866-810-1462.

    Breast-feeding

    There are no data on dimethyl fumarate and its presence in human milk, effects on the breast-fed infant, or effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for dimethyl fumarate and any potential adverse effects on the breast-fed infant from dimethyl fumarate or the underlying maternal condition. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate was administered during gestation and lactation at clinically relevant doses. Although data are limited, interferon beta-1a is considered an alternative therapy. A small number of nursing mothers receiving interferon beta-1a reported no adverse effects in their partially breast-fed infants, and the amount of interferon beta-1a excreted into breast milk appears to be insignificant. Based upon breast milk samples obtained during the study, the authors estimated that the maximum weight-adjusted dosage that an infant would receive was 0.006% of the maternal dose.

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 5.0-5.0
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    leukopenia / Delayed / 10.0-10.0
    proteinuria / Delayed / 6.0-6.0
    erythema / Early / 5.0-5.0
    eosinophilia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    diarrhea / Early / 14.0-22.3
    nausea / Early / 12.0-20.7
    abdominal pain / Early / 18.0-18.0
    vomiting / Early / 9.0-9.0
    rash / Early / 8.0-8.0
    pruritus / Rapid / 8.0-8.0
    dyspepsia / Early / 5.0-5.0
    infection / Delayed / Incidence not known
    rhinorrhea / Early / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Alemtuzumab: (Major) Concomitant use of dimethyl fumarate with alemtuzumab may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Diroximel Fumarate: (Contraindicated) Coadministration of diroximel fumarate with dimethyl fumarate is contraindicated. These agents are closely related. Use together may lead to severe GI intolerance, immunosuppression, or hepatotoxicity.
    Monomethyl Fumarate: (Contraindicated) Coadministration of monomethyl fumarate with dimethyl fumarate is contraindicated. Dimethyl fumarate is a prodrug of monomethyl fumarate. Monomethyl fumarate may be initiated the day following discontinuation of dimethyl fumarate. Use of these drugs together may lead to severe GI intolerance, immunosuppression, or hepatotoxicity.
    Ocrelizumab: (Moderate) Ocrelizumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as dimethyl fumarate. Concomitant use of ocrelizumab with dimethyl fumarate may increase the risk of immunosuppression. Avoid the use of these drugs together.
    Ofatumumab: (Moderate) Concomitant use of ofatumumab with dimethyl fumarate may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as dimethyl fumarate. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Ozanimod: (Moderate) Concomitant use of ozanimod with dimethyl fumarate may increase the risk of immunosuppression. Ozanimod has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well-controlled studies of the use of dimethyl fumarate in pregnant women exist, but animal studies showed adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function when dimethyl fumarate was administered during pregnancy at clinically relevant doses. Animal reproductive studies are not always predictive of human response. Only use dimethyl fumarate during pregnancy if the potential benefit justifies the potential risk to the fetus. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to dimethyl fumarate; information about the registry can be obtained at www.tecfiderapregnancyregistry.com or by calling 1-866-810-1462.

    There are no data on dimethyl fumarate and its presence in human milk, effects on the breast-fed infant, or effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for dimethyl fumarate and any potential adverse effects on the breast-fed infant from dimethyl fumarate or the underlying maternal condition. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate was administered during gestation and lactation at clinically relevant doses. Although data are limited, interferon beta-1a is considered an alternative therapy. A small number of nursing mothers receiving interferon beta-1a reported no adverse effects in their partially breast-fed infants, and the amount of interferon beta-1a excreted into breast milk appears to be insignificant. Based upon breast milk samples obtained during the study, the authors estimated that the maximum weight-adjusted dosage that an infant would receive was 0.006% of the maternal dose.

    MECHANISM OF ACTION

    Inflammation and oxidative stress are central pathologic factors in multiple sclerosis. Dimethyl fumarate has beneficial effects on both factors. In regard to oxidative stress, dimethyl fumarate and its active metabolite monomethyl fumarate induce the nuclear 1 factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway, which is the primary cellular defense against the cytotoxic effects of oxidative stress such as oxidative-stress-related neuronal death and damage to myelin in the CNS. Expression of antioxidant proteins is induced. Dimethyl fumarate may also improve mitochondrial function. In vitro, dimethyl fumarate increased cellular redox potential, glutathione, ATP concentrations, and mitochondrial membrane potential in a concentration-dependent manner. Also, significantly improved astrocyte and neuron cell viability after toxic oxidative challenge was noted with dimethyl fumarate in a concentration-dependent manner. In mice with experimental autoimmune encephalomyelitis, dimethyl fumarate reduced oxidative damage and consequential nerve fiber demyelination, which resulted in greater axonal preservation and improved motor function.
    In regard to inflammation, dimethyl fumarate may modulate immune cell responses by shifting dendritic-cell differentiation. Immune deviation based on the active induction of auto reactive Th2 cells is a valid approach for the treatment of inflammatory autoimmune diseases mediated by auto reactive Th1 and Th17 cells such as multiple sclerosis. Intracellular concentrations of glutathione (GSH), the main intracellular reactive oxygen species scavenger, determine whether immune responses differentiate into either a Th1/Th17 or a Th2 phenotype. Dimethyl fumarate depletes GSH, and GSH depletion induces type II dendritic cells by affecting two distinct signaling cascades: induction of HO-1 impairs production of IL-23, whereas silencing of STAT1 phosphorylation impairs IL-12 production. Induction of type II dendritic cells leads to the induction of Th2 cells and the inhibition of Th1/Th17 cells. In addition to shifting dendritic-cell differentiation, dimethyl fumarate may modulate immune cell responses by suppressing pro-inflammatory-cytokine production or directly inhibiting pro-inflammatory pathways. For example, dimethyl fumarate prevents the nuclear entry of activated NF-kappaB, and activation of NF-kappaB by pro-inflammatory stimuli leads to the expression of genes inducing and maintaining inflammation.

    PHARMACOKINETICS

    Dimethyl fumarate is administered orally. After oral administration, dimethyl fumarate is not quantifiable in plasma because it undergoes rapid pre-systemic hydrolysis by esterases that are ubiquitous in the gastrointestinal tract, blood, and tissues and is converted to its active metabolite monomethyl fumarate (MMF). Thus, all pharmacokinetic analyses were performed with plasma MMF concentrations. Among healthy volunteers and patients with multiple sclerosis, plasma protein binding of MMF is 27-45% and is independent of concentration. Metabolism of MMF occurs through the tricarboxylic acid cycle; the cytochrome P450 system is not involved. MMF, fumaric acid, citric acid, and glucose are the major metabolites in plasma. The primary route of elimination is exhalation of CO2, which accounts for approximately 60% of a dimethyl fumerate dose. Renal elimination accounts for 16% of a dose, and fecal elimination accounts for 1% of the dose. Trace amounts of unchanged MMF are present in urine. The terminal half-life of MMF is approximately 1 hour, and no circulating MMF is present at 24 hours in most individuals. Accumulation of MMF does not occur with multiple dimethyl fumarate doses.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None

    Oral Route

    After oral administration, dimethyl fumarate is not quantifiable in plasma because it undergoes rapid pre-systemic hydrolysis and is converted to its active metabolite monomethyl fumarate (MMF) by esterases that are ubiquitous in the gastrointestinal tract, blood, and tissues. Thus, all pharmacokinetic analyses were performed with plasma MMF concentrations. The median Tmax of MMF is 2—2.5 hours. The Cmax and AUC increase approximately dose proportionally in the dose range of 120—360 mg. After oral receipt of 240 mg twice a day with food to patients with multiple sclerosis, the mean Cmax of MMF was 1.87 mg/L, and the AUC was 8.21 mg*hr/L. A high-fat, high-calorie meal did not affect the AUC of MMF but decreased its Cmax by 40% and delayed the Tmax from 2 hours to 5.5 hours. Dimethyl fumarate may be taken with or without food.